The insulin-like growth factor 1 receptor (IGF-1R) is a membrane-spanning tyrosine kinase. It is a hetero-tetrameric complex consisting of two extracellular α chains and two membrane-spanning β chains, which are interconnected by several disulphide bridges. Binding of insulin-like growth factor 1 (IGF-1), and to a lesser extent insulin-like growth factor 2 and insulin, activates the receptor and leads to an autophosphorylation of tyrosines in the intracellular kinase domain in the β-chains. The activated receptor subsequently submits a mitogenic signal through, among others, the ras signaling pathway (McCormick, Nature 363:15-16 (1993)).
IGF-1R is expressed in most cell types and involved in cell growth, but it is not an absolute requirement for growth (Baker et al, Cell 75:73-82 (1993); Sell et al, Mol Cell Biol 14:3604-3612 (1994)). The over-expression and hyperactivation of IGF-1R, however, is implicated in transformation and tumorigenesis. Increased expression of IGF-1R has been observed in many human malignancies, including carcinomas of the lung, breast, thyroid, gastrointestinal tract and prostate, glioblastomas, neuroblastomas, rhabdomyosarcomas and leukemias (Macaulay, Br J Cancer 65:311-320 (1992)). IGF-1R also functions as a positive regulator of the invasive/metastatic phenotype (Long et al, Exp Cell Res 238:116-121 (1998)). Based on those features, IGF-1R is an attractive target for cancer therapy. A number of antibodies to IGF-1R have been developed, and some of them have been found to block IGF-1 binding and inhibit growth of several cancer cells (Rohlik et al, Biochem Biophys Res Commun 149:276-281 (1987); Scotlandi et al, Cancer Res58:4127-4131 (1998)). It was also able to enhance the antitumor activity of conventional chemotherapy (Benini et al, Clin Cancer Res 7:1790-1797 (2001)). The mouse monoclonal antibodies MAB 391 and mAb 4G11 were able to down-regulate IGF-1R expression (Hailey et al, Mol Cancer Ther 1:1349-1353 (2002); Jackson-Booth et al, Horm Metab Res 35:850-856 (2003)) and cause reversal of tumor phenotype (Burtrum et al, Cancer Res 63:8912-8921 (2003)). An engineered humanized antibody, mAb1H7, was shown to suppress tumor growth of MCF7 xenografts (Sachdev et al, Cancer Res 63:627-635 (2003)). The fully human antibody A12 could block IGF-1 binding, deactivating IGF-1R and inducing receptor degradation (Burtrum et al, supra). One antibody (CP-751,871) is currently subject to a phase I clinical trial for the treatment of multiple myeloma (Miller et al, Cancer Res 65:10123-10127 (2005)).
Despite the comparable success of currently used IGF-1R antibodies, a substantial number of important questions remain concerning the future of this strategy. As a consequence, the continued provision of agents with a comparable affinity for IGF-1R remains a matter of substantial interest within the field, as well as the provision of uses of such molecules in the treatment and diagnosis of disease. It is therefore an object of the invention to provide new IGF-1R-binding agents, that could for example be used for diagnostic, in vitro or in vivo imaging, and therapeutic applications.